1. Funding Legend
This invention was produced in part using funds through grant No. P-1435 from the Robert A. Welch Foundation.
2. Field of the Invention
The present invention relates generally to the field of chemistry and drug therapy. More particularly, the present invention provides novel bis-H-phosphinic acid derivatives and methods of producing bis-H-phosphinic acid derivatives. The present invention also provides methods of producing drug or protein conjugates using bis-H-phosphinic acid derivatives and methods of treating bone-related and various other diseases using such derivatives or conjugates.
3. Description of Related Art
Bisphosphonates are used to target molecules to the bone. Pharmaceutical compounds derived from bisphosphonates are used to treat bone cancer, bone infection or deliver steroids to the bone to treat osteoporosis. Bisphosphonates are not only important drugs for the treatment of bone-related diseases, but also important drugs for various other diseases such as high cholesterol. They are currently $1 billion market worldwide. Although they are generally 1-hydroxy-substituted, these compounds have a major limitation. That is, they display poor oral bioavailability because most of the compounds are excreted. Also high dosage causes serious side effects.
Several pharmaceutical companies have been trying to modify bisphosphonates to improve their biological activities. The approach commonly used is to mask the charge of the phosphonate to increase penetration through membranes. However, extensive manipulation is required to modify bisphosphonates which have 3-4 charges at physiological pH.
Bisphosphinates (or phosphinic acid derivatives) are precursors to bisphosphonates. Presently, bisphosphinates oxidize into corresponding bisphosphonates by cumbersome multistep synthesis. Bisphosphinates have been prepared under radial conditions. For example, Nifant""ev (J. Gen. Chem. USSR 1986, 56, 680) taught reacting sodium hypophosphite or hypophosphorous acid with alkynes in the presence of peroxides and extensive heat to prepare biophosphinates. Low yields of 1,2-bis-H-phosphinates were sometime obtained from Nifant""ev""s method.
Therefore, there is an increasing need for a simple, expeditious and effective method for synthesizing bisphosphonates with increased bioavailability.
With the foregoing in mind, the present invention provides a novel class of compounds, i.e., 1,1-bis-H-phosphinates (or 1,1-bis-H-phosphinic acid derivatives). Also, the present invention provides a novel method for producing 1,1-bis-H-phosphinates. These compounds are used as precursors of bisphosphonates through chemical or in vivo biological oxidation.
In one embodiment of the present invention, there is provided a 1,1 -bis-H-phosphinate compound having a structure of 
In the structure, R includes Na, H, PhNH3 and alkyl, and Rxe2x80x2 includes alkyl, COOH, NH2, epoxide, OH, CHO, SH, CH2NH2, CH2 COO-steroid, CH2-famesyl, CH2-geranyl, N-fluoroquinolones, CH2 S-albumin and NMe2CF2COOH. Preferably, this compound is a 1,1-bis-H-phosphinate.
In another embodiment of the present invention, there is provided a method for producing a bis-H-phosphinate compound. In this method, a hypophosphorous derivative reacts with an alkyne in the presence of a radical initiator at ambient temperature and pressure conditions. The reaction can be carried out, for example, at room temperature in an open container. Preferably, the radical initiator is an organoborane catalyst, for example, triethylborane.
In still another embodiment of the present invention, there is provided a method for producing a bis-H-phosphinate conjugate. In this method, a hypophosphorous derivative first reacts with an alkyne in the presence of a radical initiator at room temperature in an open container to produce a bis-H-phosphinate compound. The bis-H-phosphinate then reacts with a compound having a pendant functional group to produce a bis-H-phosphinate conjugate. Preferably, the compound having a pendant functional group is a pharmaceutical compound or a protein. An example of the functional group is an alkyne group.
In yet another embodiment of the present invention, there is provided a method for treating an individual having a bone-related disease by administering to the individual an effective dose of a bis-H-phosphinate compound or a bis-H-phosphinate conjugate. Same compound or conjugate can also be used for treating an individual having high cholesterol.